4 to 6 cycles until maximal response. Cycle frequency may be 21 to 28 days.

Notes:

Bisphosphonates should be considered in all patients with symptomatic myeloma requiring treatment. For patients with newly diagnosed symptomatic myeloma, zoledronic acid or pamidronate should be considered for monthly administration (renally adjusted) for up to 2 years. A longer duration of therapy may be appropriate (MRC M IX trial).r

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

4 to 6 cycles until maximal response. Cycle frequency may be 21 to 28 days.

Notes:

Bisphosphonates should be considered in all patients with symptomatic myeloma requiring treatment. For patients with newly diagnosed symptomatic myeloma, zoledronic acid or pamidronate should be considered for monthly administration (renally adjusted) for up to 2 years. A longer duration of therapy may be appropriate (MRC M IX trial).r

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required.

As a steroid has been included as part of this protocol, additional antiemetic steroids are not required.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Assess prior to each treatment. Based on clinical findings, temporary omission, dose reduction or cessation of the vinca alkaloid may be indicated; review by medical officer before commencing treatment.

Prescribe prophylactic laxatives to prevent constipation related to the use of vinca alkaloids.

Bisphosphonates and dental review

Caution should be taken with prolonged use of bisphosphonates due to the risk of osteonecrosis of the jaw (ONJ). A dental review prior to treatment is recommended, and all dental issues treated before the initiation of bisphosphonates. Dental review 6 to 12 monthly during treatment is advisable to minimise risk of ONJ. Concurrent daily oral supplements of calcium 500 mg and vitamin D 400 International Units are recommended.

Prednisolone, dexamethasone or methylprednisolone administered continuously for longer periods of time or for short, high-dose treatment courses that are repeated regularly (e.g. dexamethasone 40 mg daily for 4 days, or prednisone 100 mg daily for 5 days) may be associated with adverse effects.

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity

ANC less than 1 x 109/L or if platelet count less than 50 x 109/L

Omit day 8 and day 15 cyclophosphamide unless low counts are due to marrow infiltration

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.

Digoxin

Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin

Monitor digoxin serum levels; adjust digoxin dosage as appropriate

Antiepileptics

Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity

Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy

Diminished response to vaccines and increased risk of infection with live vaccines

Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Prophylaxis medications

Patient information

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)

Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet. It is associated with several classes of antineoplastic agents. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Anthracyclines are the most frequently implicated antineoplastic agents associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses.

Barlogie et al (1984) pioneered the concept of infusional vincristine and doxorubicin (VA) for the treatment of advanced myeloma.r 14 out of 20 patients with disease resistance to alkylating agents and a further 3 (of 9) patients who had disease resistance to doxorubicin, had a rapid, >75% reduction in tumour mass. Forgeson et al (1988) investigated the addition of methylprednisolone to infusional VA (VAMP) and showed similarly impressive results in previously treated patients with myeloma.r

The study by Raje et al (1997) added cyclophosphamide (C-VAMP) with the aim of increasing tumour cell susceptibility to VAMP in chemotherapy naive patients with multiple myeloma. Two sequential groups of non-selected and newly diagnosed patients, one being treated with C-VAMP and the other with VAMP were compared between April 1985 and March 1994. 204 patients, in all, were treated over this time - 75 received VAMP and 129 received C-VAMP (note, 38 of the C-VAMP patients also received verapamil though this showed no demonstrable clinical effect).r

Efficacy

Overall 71% of patients showed an objective CR/PR to the treatment and a total of 31 (17%) patients achieved CR. The patients who received C-VAMP had a significantly higher CR rate 24% of vs 8% than those who received VAMP alone (P = 0.04) a factor which the authors attribute to the added cyclophosphamide. The median number of treatment courses to achieve maximal response was 5 in both groups. There was no difference in outcome for patients who did not complete the three doses of cyclophosphamide because of myelotoxicity as compared to those who did.r

Toxicity

The protocol was well tolerated with some patients continuing to work during treatment. Mild paraesthesia related to vincristine occurred in most patients, but objective neuropathy was not common. 31% required antibiotic treatment for infection; of these 10.8% were hospitalized. 9 patients died from infection. There was an overall incidence of 7% Grade IV haematological toxicity, similar in both groups.r

Bibliography

PURPOSE: Patients with multiple myeloma are at increased risk for bacterial infection. During the first 2 months of initial chemotherapy the rate of infection is twice that experienced during the remainder of the disease course. As many as one-third of these early infections are fatal, and many more prevent adequate administration of chemotherapy. This study was designed to determine whether the morbidity and mortality of early infection can be prevented by prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX). PATIENTS AND METHODS: Eligible patients about to begin chemotherapy for multiple myeloma were randomly assigned to prophylaxis for 2 months or to no prophylaxis (control). Antibiotic prophylaxis consisted of TMP-SMX 160/800 mg orally every 12 hours administered for the first 2 months of initial chemotherapy. All patients were observed for infection for 3 months after the start of chemotherapy. RESULTS: Of 57 patients entered into the study, 54 were evaluable, representing 13.1 patient-years of observation. The 28 TMP-SMX patients and 26 control patients were comparable in terms of chemotherapy regimen, age, gender, stage, and bone marrow function. Bacterial infection during the 3-month study period occurred in 11 control patients but in only 2 patients assigned TMP-SMX (P = 0.004). Eight severe infections occurred in controls compared with 1 in a TMP-SMX patient (P = 0.010) leading to 4 and 1 infection deaths, respectively (P = not significant). Severe infections included 5 pneumonias (3 with sepsis), 2 urinary tract infections with complicating pneumonia or sepsis, 1 diverticulitis with perforation, and 1 staphylococcal scalded skin syndrome. None of the 4 nonbacterial infections was severe. The rate of bacterial infection was 2.43 per patient-year for controls and 0.29 per patient-year for the TMP-SMX group (P = 0.001). Toxicity (skin rash 6 patients, nausea 1 patient) was not life-threatening but required discontinuation of TMP-SMX in 25% of patients. CONCLUSION: Administering TMP-SMX for the first 2 months of initial chemotherapy is effective, inexpensive prophylaxis for early bacterial infection in multiple myeloma

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